The present invention relates to novel 7,8-bicycloalkyl-chroman derivatives, pharmaceutical formulations containing them, and their uses as therapeutic agents, and syntheses therefor.
Cerebral ischemia or stroke refers to the severe diminution or cessation of blood flow to all or part of the brain. Cerebral ischemia can occur as a result of a number of causes or insults, including, but not limited to cerebrovascular occlusion, thromboembolytic insult, cardiac failure and hemorrhagic accident. It is now known that pharmacologic intervention, if provided within a reasonable interval of the initial insult, can significantly reduce cerebral tissue death following cerebral ischemia.
The use of certain chroman-ylmethylamino derivatives for the treatment of Parkinson's disease and epilepsy has been disclosed in U.S. Pat. Nos. 5,663,294; 5,541,199; 5,670,667; 5,684,039; 5,756,521; 6,235,774; and 6,331,561. The use of chromans for treating mitochondria associated diseases including Alzheimer's disease, diabetes mellitus, Parkinson's disease, neuronal and cardiac ischemia, Huntington's disease, and stroke is disclosed in U.S. Pat. Nos. 6,498,191 and 6,511,966 and US patent application US 2003/0176448. Triphenyl phosphonium tocopherol analogs having cardioprotective or mitochondrially targeted antioxidant properties have been described by Gisar, J M in EP 545,283 and by Murphy, M. in Annals of the New York Academy of Sciences (2002), 959, 263-274 and in U.S. Pat. No. 6,331,532, US 2202/00523242 and US 2003/0069208. These applications neither teach nor suggest the 7,8-bicycloalkyl-chromans derivatives described in this invention.
The use of antioxidants targeted to mitochondria shown to be effective at slowing disease progression has been reported by Jauslin, M L in FASEB Journal, express article 10.1096/fj.03-0240fje. Therapeutic benefit of administering γ-tocopherol derivatives and metabolites as antioxidants and nitrogen oxide scavengers which treat high blood pressure, thromboembolic diseases, cardiovascular disease, cancer, natriuretic disease, formation of neuropathological lesion and reduced immune system response are disclosed in U.S. Pat. Nos. 6,555,575; 6,242,479; 6,150,402; and 6,410,589. The use of certain chroman derivatives in cosmetic and dermatological preparations is disclosed in US 2002/0127252. Beneficial effects of Vitamin E in the progression of a number of major degenerative diseases of the nervous system is examined in Fryer, Nutritional Neuroscience, (1998) Vol. 1, 327-351. Reduction of the inflammation marker CRP with 6-hydroxy chromans and with tocopherols has been disclosed in commonly owned U.S. patent applications 60/426,764 and US 2003/0100603, but these applications neither teach nor suggest the use of 7,8-bicycloalkyl-chromans derivatives described in this invention.
The present invention addresses the desire to provide new therapies for conditions that affect millions of people, and particularly for conditions characterized by neuroprotection, neuroinflammation, cognitive disorders, neurodegenerative and/or mitochondrial dysfunction conditions with novel 7,8-bicyloalkyl-chroman derivatives of Formula I. There remains a need for providing protection with agents that are effective even if first administered after a significant time (e.g. about 5 hours) following an ischemic or oxidative insult. The compounds of the present invention address this need.